Early detection of solid organ graft rejection or graft injury is a significant unmet clinical need. Biopsy-based methods have poor sensitivity and high risk of severe complications. Therefore especially attractive are non-invasive tests that do not require a biopsy of the transplanted organ. Currently, detection of serum creatinine is a non-invasive test for graft rejection or injury. However, the test is not very specific. Additionally, detectable elevation of this marker occurs relatively late in the course of graft rejection when it is often too late to save the organ.
There have been several attempts to develop a nucleic acid-based non-invasive method for detecting graft rejection. Some methods relied on signals of graft rejection such as expression of certain rejection-associated genes. See e.g., Hartono et al., (2011) Non-invasive Diagnosis of Acute Rejection of Renal Allografts. Curr Opin Organ Transplant 15:35. There also have been attempts to look at donor-specific nucleic acids in the recipient's blood. Those were initially limited to Y-chromosome genes detected in female recipients of male-donated organs. Morelra et al., (2009) Cell-free DNA as non-invasive acute rejection marker in renal transplantation. Clin. Chem. 55:11; Snyder et al., (2011) Universal noninvasive detection of solid organ transplant rejection. PNAS 108:6229. There were also early attempts to detect donor-specific HLA sequences in the recipient's plasma. Gadi et al., (2006) Soluble donor DNA concentrations in recipient's serum correlate with pancreas-kidney rejection. Clin. Chem. 52:3. However, these attempts were widely criticized as unsuccessful: predictive value of the test was poor as there was enormous variation in the signal within each group of patients. (Reviewed in Baxter-Lowe, L., and Busch, M., (2006) Tracking Microchimeric DNA in Plasma to Diagnose and Manage Organ Transplant Rejection Clin Chem 52:4.) To date, there is no reliable non-invasive test for early detection of graft rejection.